Cysteamine Chemisorption at Mercury-Solution Interfaces in the Context of Redox and Microdissociation Equilibria.

The redox behavior and chemisorption of cysteamine (CA) at a charged mercury surface are described, with an emphasis on its acid-base properties supported by molecular dynamics and quantum mechanical calculations. It was found that CA forms chemisorbed layers on the surface of the mercury electrode. The formation of Hg-CA complexes is connected to mercury disproportionation, as reflected in peaks SII and SI at potentials higher than the electrode potential of zero charge (p.z.c.). Both the process of chemisorption of CA and its consequent redox transformation are proton-dependent. Also, depending on the protonation of CA, the formation of typical populations of chemisorbed conformers can be observed. In addition, cystamine (CA disulfide dimer) can be reduced on the mercury surface. Between the potentials of this reduction and peak SI, the p.z.c. of the electrode used can be found. Furthermore, CA can serve as an LMW catalyst for hydrogen evolution. The mechanistic insights presented here can be used for follow-up research on CA chemisorption and targeted modification of other metallic surfaces.

Hexahelicene DNA-binding: Minor groove selectivity, semi-intercalation and chiral recognition.

In this contribution, we focused on a fundamental study targeting the interaction of water-soluble [6]helicene derivative 1 (1-butyl-3-(2-methyl[6]helicenyl)-imidazolium bromide) with double-stranded (ds) DNA. A synthetic 30-base pair duplex, plasmid, chromosomal calf thymus and salmon DNA were investigated using electrochemistry, electrophoresis and spectroscopic tools supported by molecular dynamics (MD) and quantum mechanical approaches. Both experimental and theoretical work revealed the minor groove binding of 1 to the dsDNA. Both the positively charged imidazole ring and hydrophobic part of the side chain contributed to the accommodation of 1 into the dsDNA structure. Neither intercalation into the duplex DNA nor the stable binding of 1 to single-stranded DNA were found in topoisomerase relaxation experiments with structural components of 1, i.e. [6]helicene (2) and 1-butyl-3-methylimidazolium bromide (3), nor by theoretical calculations. Finally, the binding of optically pure enantiomers (P)-1 and (M)-1 was studied using circular dichroism spectroscopy, isothermal titration calorimetry and UV Resonance Raman (UVRR) methods. Using MD and quantum mechanical methods, minor groove and semi-intercalation were proposed for compound 1 as the predominant binding modes. From the UVRR findings, we also can conclude that 1 tends to preferentially interact with adenine and guanine residues in the structure of dsDNA.

Cubosomal lipid formulation of nitroalkene fatty acids: Preparation, stability and biological effects.

Lipid nitroalkenes - nitro-fatty acids (NO2-FAs) are formed in vivo via the interaction of reactive nitrogen species with unsaturated fatty acids. The resulting electrophilic NO2-FAs play an important role in redox homeostasis and cellular stress response. This study investigated the physicochemical properties and reactivity of two NO2-FAs: 9/10-nitrooleic acid (1) and its newly prepared 1-monoacyl ester, (E)-2,3-hydroxypropyl 9/10-nitrooctadec-9-enoate (2), both synthesized by a direct radical nitration approach. Compounds 1 and 2 were investigated in an aqueous medium and after incorporation into lipid nanoparticles prepared from 1-monoolein, cubosomes 1@CUB and 2@CUB. Using an electrochemical analysis and LC-MS, free 1 and 2 were found to be unstable under acidic conditions, and their degradation occurred in an aqueous environment within a few minutes or hours. This degradation was associated with the production of the NO radical, as confirmed by fluorescence assay. In contrast, preparations 1@CUB and 2@CUB exhibited a significant increase in the stability of the loaded 1 and 2 up to several days to weeks. In addition to experimental data, density functional theory-based calculation results on the electronic structure and structural variability (open and closed configuration) of 1 and 2 were obtained. Finally, experiments with a human HaCaT keratinocyte cell line demonstrated the ability of 1@CUB and 2@CUB to penetrate through the cytoplasmic membrane and modulate cellular pathways, which was exemplified by the Keap1 protein level monitoring. Free 1 and 2 and the cubosomes prepared from them showed cytotoxic effect on HaCaT cells with IC50 values ranging from 1 to 8 µM after 24 h. The further development of cubosomal preparations with embedded electrophilic NO2-FAs may not only contribute to the field of fundamental research, but also to their application using an optimized lipid delivery vehicle.

Antioxidant function of phytocannabinoids: Molecular basis of their stability and cytoprotective properties under UV-irradiation.

In this contribution, a comprehensive study of the redox transformation, electronic structure, stability and photoprotective properties of phytocannabinoids is presented. The non-psychotropic cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and psychotropic tetrahydrocannabinol (THC) isomers and iso-THC were included in the study. The results show that under aqueous ambient conditions at pH 7.4, non-psychotropic cannabinoids are slight or moderate electron-donors and they are relatively stable, in the following order: CBD > CBG ≥ CBN > CBC. In contrast, psychotropic Δ9-THC degrades approximately one order of magnitude faster than CBD. The degradation (oxidation) is associated with the transformation of OH groups and changes in the double-bond system of the investigated molecules. The satisfactory stability of cannabinoids is associated with the fact that their OH groups are fully protonated at pH 7.4 (pKa is ≥ 9). The instability of CBN and CBC was accelerated after exposure to UVA radiation, with CBD (or CBG) being stable for up to 24 h. To support their topical applications, an in vitro dermatological comparative study of cytotoxic, phototoxic and UVA or UVB photoprotective effects using normal human dermal fibroblasts (NHDF) and keratinocytes (HaCaT) was done. NHDF are approx. twice as sensitive to the cannabinoids' toxicity as HaCaT. Specifically, toxicity IC50 values for CBD after 24 h of incubation are 7.1 and 12.8 µM for NHDF and HaCaT, respectively. None of the studied cannabinoids were phototoxic. Extensive testing has shown that CBD is the most effective protectant against UVA radiation of the studied cannabinoids. For UVB radiation, CBN was the most effective. The results acquired could be used for further redox biology studies on phytocannabinoids and evaluations of their mechanism of action at the molecular level. Furthermore, the UVA and UVB photoprotectivity of phytocannabinoids could also be utilized in the development of new cannabinoid-based topical preparations.

Electrophilic characteristics and aqueous behavior of fatty acid nitroalkenes.

Fatty acid nitroalkenes (NO2-FA) are endogenously-generated products of the reaction of metabolic and inflammatory-derived nitrogen dioxide (.NO2) with unsaturated fatty acids. These species mediate signaling actions and induce adaptive responses in preclinical models of inflammatory and metabolic diseases. The nitroalkene substituent possesses an electrophilic nature, resulting in rapid and reversible reactions with biological nucleophiles such as cysteine, thus supporting post-translational modifications (PTM) of proteins having susceptible nucleophilic centers. These reactions contribute to enzyme regulation, modulation of inflammation and cell proliferation and the regulation of gene expression responses. Herein, focus is placed on the reduction-oxidation (redox) characteristics and stability of specific NO2-FA regioisomers having biological and clinical relevance; nitro-oleic acid (NO2-OA), bis-allylic nitro-linoleic acid (NO2-LA) and the conjugated diene-containing nitro-conjugated linoleic acid (NO2-cLA). Cyclic and alternating-current voltammetry and chronopotentiometry were used to the study of reduction potentials of these NO2-FA. R-NO2 reduction was observed around -0.8 V (vs. Ag/AgCl/3 M KCl) and is related to relative NO2-FA electrophilicity. This reduction process could be utilized for the evaluation of NO2-FA stability in aqueous milieu, shown herein to be pH dependent. In addition, electron paramagnetic resonance (EPR) spectroscopy was used to define the stability of the nitroalkene moiety under aqueous conditions, specifically under conditions where nitric oxide (.NO) release could be detected. The experimental data were supported by density functional theory calculations using 6-311++G (d,p) basis set and B3LYP functional. Based on experimental and computational approaches, the relative electrophilicities of these NO2-FA are NO2-cLA >> NO2-LA > NO2-OA. Micellarization and vesiculation largely define these biophysical characteristics in aqueous, nucleophile-free conditions. At concentrations below the critical micellar concentration (CMC), monomeric NO2-FA predominate, while at greater concentrations a micellar phase consisting of self-assembled lipid structures predominates. The CMC, determined by dynamic light scattering in 0.1 M phosphate buffer (pH 7.4) at 25 °C, was 6.9 (NO2-LA) 10.6 (NO2-OA) and 42.3 µM (NO2-cLA), respectively. In aggregate, this study provides new insight into the biophysical properties of NO2-FA that are important for better understanding the cell signaling and pharmacological potential of this class of mediators.

Redox properties and human serum albumin binding of nitro-oleic acid.

Nitro-fatty acids modulate inflammatory and metabolic stress responses, thus displaying potential as new drug candidates. Herein, we evaluate the redox behavior of nitro-oleic acid (NO2-OA) and its ability to bind to the fatty acid transporter human serum albumin (HSA). The nitro group of NO2-OA underwent electrochemical reduction at -0.75 V at pH 7.4 in an aqueous milieu. Based on observations of the R-NO2 reduction process, the stability and reactivity of NO2-OA was measured in comparison to oleic acid (OA) as the negative control. These electrochemically-based results were reinforced by computational quantum mechanical modeling. DFT calculations indicated that both the C9-NO2 and C10-NO2 positional isomers of NO2-OA occurred in two conformers with different internal angles (69° and 110°) between the methyl- and carboxylate termini. Both NO2-OA positional isomers have LUMO energies of around -0.7 eV, affirming the electrophilic properties of fatty acid nitroalkenes. In addition, the binding of NO2-OA and OA with HSA revealed a molar ratio of ~7:1 [NO2-OA]:[HSA]. These binding experiments were performed using both an electrocatalytic approach and electron paramagnetic resonance (EPR) spectroscopy using 16-doxyl stearic acid. Using a Fe(DTCS)2 spin-trap, EPR studies also showed that the release of the nitro moiety of NO2-OA resulted in the formation of nitric oxide radical. Finally, the interaction of NO2-OA with HSA was monitored via Tyr and Trp residue electro-oxidation. The results indicate that not only non-covalent binding but also NO2-OA-HSA adduction mechanisms should be taken into consideration. This study of the redox properties of NO2-OA is applicable to the characterization of other electrophilic mediators of biological and pharmacological relevance.

Oxalic Acid Adsorption on Rutile: Molecular Dynamics and ab Initio Calculations.

Detailed analysis of the adsorption of oxalic acid ions, that is, oxalate and hydrogenoxalate, on the rutile (110) surface was carried out using molecular dynamics augmented by free energy calculations and supported by ab initio calculations. The predicted adsorption on perfect nonhydroxylated and hydroxylated surfaces with surface charge density from neutral to +0.208 C/m2 corresponding to pH values of about 6 and 3.7, respectively, agrees with experimental adsorption data and charge-distribution multisite ion complexation model predictions obtained using the most favorable surface complexes identified in our simulations. We found that outer-sphere complexes are the most favorable, owing to strong hydrogen binding of oxalic acid ions with surface hydroxyls and physisorbed water. The monodentate complex, the most stable among inner-sphere complexes, was about 15 kJ/mol higher in energy, but separated by a large energy barrier. Other inner-sphere complexes, including some previously suggested in the literature as likely adsorption structures such as bidentate and chelate complexes, were found to be unstable both by classical and by ab initio modeling. Both the surfaces and (hydrogen)oxalate ions were modeled using charges scaled to 75% of the nominal values in accord with the electronic continuum theory and our earlier parameterization of (hydrogen)oxalate ions, which showed that nominal charges exaggerate ion-water interactions.

Structural Stability of Peptidic His-Containing Proton Wire in Solution and in the Adsorbed State.

Molecular wires are functional molecules applicable in the field of transfer processes in technological and biochemical applications. Besides molecular wires with the ability to transfer electrons, research is currently focused on molecular wires with high proton affinity and proton transfer ability. Recently, proposed peptidic proton wires (H wires) are one example. Their ability to mediate the transport of protons from aqueous solutions onto the surface of a Hg electrode in a catalytic hydrogen evolution reaction was investigated by constant-current chronopotentiometric stripping. However, elucidating the structure of H wires and rationalizing their stability are key requirements for their further research and application. In this article, we focus on the His (H) and Ala (A)-containing peptidic H wire A3-(H-A2)6 in solution and after its immobilization onto the electrode surface in the presence of the secondary structure stabilizer 2,2,2-trifluoroethanol (TFE). We found that the solvent containing more than 25% of TFE stabilizes the helical structure of A3-(H-A2)6 not only in solution but also in the adsorbed state. The TFE efficacy to stabilize α-helical structure was confirmed using high-resolution nuclear magnetic resonance, circular dichroism, and molecular dynamics simulation. Experimental and theoretical results indicated A3-(H-A2)6 to be a high proton-affinity peptidic H wire with an α-helical structure stabilized by TFE, which was confirmed in a comparative study with hexahistidine as an example of a peptide with a definitely disordered and random coil structure. The results presented here could be used for further investigation of the peptidic H wires and for the application of electrochemical methods in the research of proton transfer phenomena in general.

Force field parametrization of hydrogenoxalate and oxalate anions with scaled charges.

Models of the hydrogenoxalate (bioxalate, charge -1) and oxalate (charge -2) anions were developed for classical molecular dynamics (CMD) simulations and parametrized against ab initio molecular dynamics (AIMD) data from our previous study (Kroutil et al. (2016) J Mol Model 22:210). The interactions of the anions with water were described using charges scaled according to the electronic continuum correction approach with rescaling of nonbonded parameters (ECCR), and those descriptions of anion interactions were found to agree well with relevant AIMD and experimental results. The models with full RESP charges showed excessively strong electrostatic interactions between the solute and water molecules, leading to an overstructured solvation shell around the anions and thus to a diffusion coefficient that was much too low. The effect of charge scaling was more evident for the oxalate dianion than for the hydrogenoxalate anion. Our work provides CMD models for ions of oxalic acid and extends previous studies that showed the importance of ECCR for modeling divalent ions and ions of organic compounds. Graphical abstract The radial distribution function between a water oxygen (Ow) and an oxygen of the oxalate dianion (Ox) significantly improved when scaled charges were applied to the anion.

The cyanobacterial metabolite nocuolin a is a natural oxadiazine that triggers apoptosis in human cancer cells.

Oxadiazines are heterocyclic compounds containing N-N-O or N-N-C-O system within a six membered ring. These structures have been up to now exclusively prepared via organic synthesis. Here, we report the discovery of a natural oxadiazine nocuolin A (NoA) that has a unique structure based on 1,2,3-oxadiazine. We have identified this compound in three independent cyanobacterial strains of genera Nostoc, Nodularia, and Anabaena and recognized the putative gene clusters for NoA biosynthesis in their genomes. Its structure was characterized using a combination of NMR, HRMS and FTIR methods. The compound was first isolated as a positive hit during screening for apoptotic inducers in crude cyanobacterial extracts. We demonstrated that NoA-induced cell death has attributes of caspase-dependent apoptosis. Moreover, NoA exhibits a potent anti-proliferative activity (0.7-4.5 µM) against several human cancer lines, with p53-mutated cell lines being even more sensitive. Since cancers bearing p53 mutations are resistant to several conventional anti-cancer drugs, NoA may offer a new scaffold for the development of drugs that have the potential to target tumor cells independent of their p53 status. As no analogous type of compound was previously described in the nature, NoA establishes a novel class of bioactive secondary metabolites.

Structure and dynamics of solvated hydrogenoxalate and oxalate anions: a theoretical study.

Hydrogenoxalate (charge -1) and oxalate (charge -2) anions and their solvated forms were studied by various computational techniques. Ab initio quantum chemical calculations in gas phase, in implicit solvent and microsolvated (up to 32 water molecules) environment were performed in order to explore a potential energy surface of both anions. The solvation envelope of water molecules around them and the role of water on the conformation of the anions was revealed by means of Born-Oppenheimer molecular dynamics simulations and optimization procedures. The structure of the anions was found to be dependent on the number of water molecules in the solvation shell. A subtle interplay between intramolecular and intermolecular hydrogen bonding dictates the final conformation and thus an explicit solvent model is necessary for a proper description of this phenomena. Graphical Abstract Solvated hydrogenoxalate and oxalate anions.

Resonant Infrared Multiple Photon Dissociation Spectroscopy of Anionic Nucleotide Monophosphate Clusters.

We report mid-infrared spectra and potential energy surfaces of four anionic, 2'-deoxynucleotide-5'-monophosphates (dNMPs) and the ionic DNA pairs [dGMP-dCMP-H](1-), [dAMP-dTMP-H](1-) with a total charge of the complex equal to -1. We recorded IR action spectra by resonant IR multiple-photon dissociation (IRMPD) using the FELIX free electron laser. The potential energy surface study employed an on-the-fly molecular dynamics quenching method (MD/Q), using a semiempirical AM1 method, followed by an optimization of the most stable structures using density functional theory. By employing infrared multiple-photon dissociation (IRMPD) spectroscopy in combination with high-level computational methods, we aim at a better understanding of the hydrogen bonding competition between the phosphate moieties and the nucleobases. We find that, unlike in multimer double stranded DNA structures, the hydrogen bonds in these isolated nucleotide pairs are predominantly formed between the phosphate groups. This intermolecular interaction appears to exceed the stabilization energy resulting from base pairing and directs the overall cluster structure and alignment.

Mechanism of the cis-[Pt(1R,2R-DACH)(H2O)2]2+ intrastrand binding to the double-stranded (pGpG)·(CpC) dinucleotide in aqueous solution: a computational DFT study.

A mechanism of the intrastrand 1,2-cross-link formation between the double-stranded pGpG·CpC dinucleotide (ds(pGpG)) and fully aquated oxaliplatin cis-[Pt(DACH)(H2O)2](2+) (DACH = cyclohexane-1R,2R-diamine) is presented. All structures of the reaction pathways including the transition states (TSs) were fully optimized in water solvent using DFT methodology with dispersion corrections. Both 5' → 3' and 3' → 5' binding directions were considered. In the first step there is a slight kinetic preference for 5'-guanine (5'G) monoadduct formation with an activation Gibbs free energy of 18.7 kcal/mol since the N7 center of the 5'G base is fully exposed to the solvent. On the other hand, the N7 atom of 3'-guanine (3'G) is sterically shielded by 5'G. The lowest energy path for formation of the 3'G monoadduct with an activation barrier of 19.3 kcal/mol is connected with a disruption of the 'DNA-like' structure of ds(pGpG). Monoadduct formation is the rate-determining process. The second step, chelate formation, is kinetically preferred in the 3' → 5' direction. The whole process of the platination is exergonic by up to -18.8 kcal/mol. Structural changes of ds(pGpG), charge transfer effects, and the influence of platination on the G·C base pair interaction strengths are also discussed in detail.

Structure of 2,4-diaminopyrimidine-theobromine alternate base pairs.

We report the structure of clusters of 2,4-diaminopyrimidine with 3,7-dimethylxanthine (theobromine) in the gas phase determined by IR-UV double resonance spectroscopy in both the near-IR and mid-IR regions in combination with ab initio computations. These clusters represent potential alternate nucleobase pairs, geometrically equivalent to guanine-cytosine. We have found the four lowest energy structures, which include the Watson-Crick base pairing motif. This Watson-Crick structure has not been observed by resonant two-photon ionization (R2PI) in the gas phase for the canonical DNA base pairs.

Isolated gramicidin peptides probed by IR spectroscopy.

We report double-resonant IR/UV ion-dip spectroscopy of neutral gramicidin peptides in the gas phase. The IR spectra of gramicidin A and C, recorded in both the 1000 cm(-1) to 1800 cm(-1) and the 2700 to 3750 cm(-1) region, allow structural analysis. By studying this broad IR range, various local intramolecular interactions are probed, and complementary IR modes can be accessed. Ab initio quantum chemical calculations are used to support the interpretation of the experimental IR spectra. The comparison of the calculated frequencies with the experimental IR spectrum probed via the strong infrared absorptions of all the amide groups (NH stretch, C=O stretch and NH bend), shows evidence for a helical structure in the gas phase, which is similar to that in the condensed phase. Additionally, we show that to improve the spectral resolution when studying large neutral molecular structures of the size of gramicidin, the use of heavier carrier gas could be advantageous.

A comparative study of the binding of QSY 21 and Rhodamine 6G fluorescence probes to DNA: structure and dynamics.

Molecular dynamics (MD) simulations and ab initio quantum chemical calculations were employed to investigate the structure, dynamics and interactions of the QSY 21 nonfluorescent quencher and the fluorescence dye Rhodamine 6G bound to a B-DNA decamer. For QSY 21, two binding motifs were observed. In the first motif, the central xanthene ring is stacked on one base of the adjacent cytosine-guanine DNA base pair, whereas one of the 2,3-dihydro-1-indolyl aromatic side rings is stacked on the other base. In the second motif, the QSY 21 stacking interaction with the DNA base pair is mediated only by one of the side rings. Several transitions between the motifs are observed during a MD simulation. The ab initio calculations show that none of these motifs is energetically preferred. Two binding motifs were found also for Rhodamine 6G, with the xanthene ring stacked predominantly either on the cytosine or on the guanine. These results suggest that the side rings of QSY 21 play a crucial role in its stacking on the DNA and indicate novel binding mode absent in the case of Rhodamine 6G, which lacks aromatic side rings.

The structure and vibrational dynamics of the pyrrole dimer.

The energy, dynamical geometry characteristics and low frequency intermolecular vibrations of the pyrrole dimer have been examined at the MP2 and CCSD(T) levels of ab initio theory. The actual distortions of the pyrrole dimer from its reference (equilibrium) position were measured using the distance of the monomer mass centres (R), the angle between their planes (the mirror planes orthogonal to the molecular planes of both monomers were assumed to coincide) and the angle between the R directional vector and the proton-accepting monomer plane; the structures of the monomers were assumed to be unchanged by dimerisation. The lowest part of the potential energy function confining the probed motions possessed two equivalent energy pockets with the CCSD(T)/complete basis set limit stabilisation energy of 6.2 kcal mol(-1) separated by a relatively low barrier (0.8 kcal mol(-1)), thus raising questions concerning the classical interconversion of the T-shaped equilibrium structures via a C(2h) parallel-displaced transient structure and/or quantum mechanical tunnellings through the barrier. The questions have been answered unequivocally by calculating the energies and tunnelling splittings of the relevant vibrational levels. Importantly: (a) all the excited tunnelling (interconverting) states underwent fast geometry interconversions, hence evidencing conformational instability of the studied dimer under usual laboratory conditions; (b) the dynamical averages of the used geometry characteristics exhibited profound tunnelling (interconverting) dependences, thus advocating that they be respected in reliable structural studies of the pyrrole dimer and chemically similar systems; (c) the geometry characteristics of the ground vibrational state agreed quite reasonably with their experimental counterparts, evidencing the adequacy of the theory used and the reliability of the characteristics predicted for the excited vibrational states; and (d) the calculated dissociation barrier of the dimer exceeds its experimentally derived analogue by more than three times, showing the inadequacy of the constraining assumptions used to derive it from the experimental spectra.

The ab initio assigning of the vibrational probing modes of tryptophan: linear shifting of approximate anharmonic frequencies vs. multiplicative scaling of harmonic frequencies.

To gain insight into the prospects for a few-dimensional ab initio quantum-mechanical description of the vibrational motions of conformationally flexible molecular systems, the NH-, NH(2)-, CO- and OH-stretching and COH-bending vibrations of the most stable tryptophan conformations have been probed using simple one- and two-dimensional anharmonic Hamiltonians and potential energy functions evaluated by means of the standard RI-MP2, CCSD(T) and DFT-D quantum chemical procedures. Although strongly dependent on the procedure used, the calculated vibrational spectral patterns have been found to be in a robust one-to-one harmony with their experimental counterparts, thus proving the adequacy of the theory used for the reliable assignment of the experimental data. Therefore, the approach appears to be a suitable tool for assigning the vibrational probing modes even of systems which are too large to be tractable by the standard normal-coordinate analysis.

Microhydration of guanine...cytosine base pairs, a theoretical Study on the role of water in stability, structure and tautomeric equilibrium.

The potential energy surfaces of guanine...cytosine complexes and microhydrated guanine...cytosine (one and two water molecules) were investigated by the molecular dynamics/quenching method (MD/Q), using the empirical potential Parm94 force field, implemented in the Amber program package. The calculations were conducted for all the possible combinations of the four most stable tautomers of guanine and three of cytosine (covering the canonical forms in both cases). The obtained structures were sorted by their structural motifs into three main groups: planar hydrogen-bonded; stacked; and T-shaped structures. The most stable structures found at the empirical potential energy surfaces were fully reoptimised at the second-order Møller-Plesset perturbation theory as well as using the density functional method with an empirical dispersion term (DFT-D). A combination of the canonical form of guanine and cytosine and canonical cytosine with a guanine tautomer where the hydrogen is switched from position N9 to N7 are energetically preferred in microsolvated systems as well as those without the presence of a solvent. The rising number of water molecules leads to smaller differences between the stability of the various combinations of the tautomers of bases in the base pairs. For some of the tautomer combinations (mainly the enol-enol combination), two water molecules are sufficient for the preference of stacked structures over the H-bonded ones. The interaction energies and geometries obtained by the second-order Møller-Plesset perturbation theory method and the much less computationally demanding DFT-D method are comparable, except for stacked complexes, where the interaction energies are overestimated on average by 3 kcal mol(-1) at the MP2 level.

Double-helical --> ladder structural transition in the B-DNA is induced by a loss of dispersion energy.

The role of the dispersion energy and electrostatic energy on the geometry and stability of the B-DNA helix was investigated. Both molecular dynamics simulations with empirical force field and hybrid quantum mechanical/molecular mechanics molecular dynamics simulations, where the dispersion or electrostatics term is suppressed/increased, on the one hand and an ab initio minimization procedure on the other have shown that the lack of the dispersion term leads to an increase of the vertical separation of the bases as well as to a loss of helicity, thus resulting in a ladder-like structure. A decrease of the electrostatic term produces a separation of the DNA strands. The biological consequences of both electrostatic and dispersion forces in DNA are enormous, and without either of them, DNA would become unstable and unable to provide the storage and transfer of genetic information.